This is an application from the University of Pennsylvania School of Medicine to participate in the Heart Failure Clinical Research Network (HF-CRN) as a regional clinical center (RCC) and as a Clinical Research Skills Development Core. Our Mid-Atlantic RCC includes Johns Hopkins University and the Lancaster Heart Group. As a composite, our sites follow a demographically diverse population of more than 6,000 patients with heart failure (HF), with more than 1,900 new referrals, 18,000 outpatient visits and 2,900 HF hospitalizations annually. The size and diversity of the existing HF patient population and referral base served by our sites will enable our RCC to identify and enroll patients in virtually any type of HF clinical research study. With this application, we propose a novel clinical trial examining the therapeutic efficacy of recombinant glucagon-like peptide (GLP-1) in patients with severe systolic HF. Recognizing that recent studies demonstrate a 30% rate of death or re-hospitalization and the failure of multiple in-hospital interventions, our study couples the logistical advantages of in-hospital enrollment with the need for a post- hospitalization intervention. The therapeutic promise of GLP-1 is based on the hypothesis that the failing heart is challenged bioenergetically and date indicating that myocardial insulin resistance is high among both diabetics and non-diabetics with severe systolic HF. Small published studies demonstrating that GLP-1 improves myocardial performance and outcomes in patients with systolic dysfunction associated with chronic heart failure, acute myocardial infarction and coronary bypass grafting further support the safety and potential efficacy of GLP-1. Each of these trials was led by Dr. Richard Shannon, the Chairman of Medicine at Penn, who will serve as a consultant for this application. In 360 randomized patients, the proposed study will examine the effect of GLP-1 on the primary endpoint of death or recurrent hospitalization and several secondary endpoints including myocardial contractile reserve assessed via dobutamine stress echocardiography, 6-minute walk distance, quality of life. This novel study of GLP-1 in a high risk population is well-suited to the organization and strength of the HF-CRN. RELEVANCE (See instructions): Heart failure is a leading cause of mortality in the U.S. that imposes a major public health and financial burden. Patients hospitalized with HF are at particular risk for poor outcomes. By evaluating promising clinical interventions, including glucagon-like peptide (GLP-1), this proposal to establish a new regional clinical center for the NHLBI Heart Failure Network will help improve the care of patients with heart failure.